Fibronectin type III domain-containing 5 improves aging-related cardiac dysfunction in mice

Area of Science:

• Cardiovascular Biology
• Aging Research
• Molecular Medicine

Background:

• Aging is a primary risk factor for cardiovascular diseases, contributing significantly to morbidity and mortality in elderly populations.
• Aging-related cardiac dysfunction is a major health concern, necessitating novel therapeutic strategies.
• Fibronectin type III domain-containing 5 (FNDC5) and its cleaved form, irisin, have shown cardioprotective effects against doxorubicin-induced cardiomyopathy.

Purpose of the Study:

• To investigate the role of FNDC5 in aging-related cardiac dysfunction.
• To determine the therapeutic potential of FNDC5 and irisin in mitigating age-related cardiac remodeling and dysfunction.
• To elucidate the underlying molecular mechanisms involving NLRP3 inflammasome and AMPKα activation.

Main Methods:

• Adeno-associated virus serotype 9 (AAV9)-mediated cardiac-specific FNDC5 overexpression in aging mice.
• Subcutaneous irisin infusion in aging mice.
• Utilized Nlrp3 and Ampkα2 global knockout mice to verify mechanistic pathways.
• Investigated FNDC5's preventive effects via long-term gene transfer in young mice.
• Examined FNDC5's role in vitro using TNF-α-stimulated neonatal rat cardiomyocytes.

Main Results:

• FNDC5 expression was found to be downregulated in aging hearts.
• Cardiac FNDC5 overexpression or irisin treatment significantly suppressed NLRP3 inflammasome and cardiac inflammation, attenuating aging-related cardiac remodeling and dysfunction.
• Irisin treatment inhibited cellular senescence in vitro, and FNDC5 activated AMPKα by preventing lysosomal degradation of GLP-1 receptor.
• Early-life FNDC5 gene transfer delayed the onset of cardiac dysfunction during aging.

Conclusions:

• FNDC5 improves aging-related cardiac dysfunction by activating AMPKα, offering a promising therapeutic target for cardiovascular health in the elderly.
• FNDC5 and its active form, irisin, demonstrate significant potential in combating age-related cardiac decline.
• Targeting FNDC5 pathways represents a viable strategy for enhancing cardiovascular resilience in aging populations.